1. Field of the Invention
The present invention relates to novel cinnamaldehyde derivatives. More particularly, the present invention relates to novel cinnamaldehyde derivatives or pharmaceutically acceptable salts thereof having improved solubility in water, a method of preparing the same, and an anticancer composition comprising the same.
2. Description of the Related Art
Division, proliferation and differentiation of cells constituting the body are vital processes for the maintenance of life phenomena. Cellular proliferation and growth necessary for maintaining the normal functions of cells are regulated through sophisticated intracellular signal transduction systems. Once cells recognize a signal from the outside, a cascade of intracellular signaling events is activated to transfer the external signal to the cellular clock within the nucleus through several proteins (PLC, PKC, Shc, Grb2, Raf, MAPK, MEK, etc.) and molecular mediators (GTP, cAMP, etc.). When an abnormality occurs in any one of the signaling events, the events are balanced by their own regulatory mechanisms, but the abnormality often leads to disease. In particular, the cell cycle, during which events happen in the nucleus of cells, is a process essential for controlling the maintenance of cells.
Like a clock, which is composed of three counters for seconds, minutes and hours, the cell cycle consists of four different phases: G1 (Gap1), S (DNA synthesis), G2 (Gap2) and M (mitosis) phases. In addition to the phases, when cells are present at a high density or exposed to low concentrations of growth factors for a long period, they enter the resting phase (G0), in which cells stop dividing. These events, occurring in the nucleus, are referred to as the cell cycle.
In a clock, a clock pendulum is driven to oscillate using electric or physical force to rotate second, minute and hour counters in clockwise directions, thereby precisely displaying the time. For this, a predetermined force should be applied to the pendulum, and many other parts are thus needed. Likewise, the cell cycle process is controlled by a complex network of surveillance mechanisms, called checkpoints, which allow for the cellular clock to proceed in a defined sequence of G1-S-G2-M phases. There are two main checkpoints: one at the G1/S transition and another at G2/M. Cell cycle checkpoints check whether requirements for cells to progress to the next phase of the cycle are satisfied. When all requirements are satisfied, cells enter the S phase or M phase. Loss of checkpoint regulatory mechanisms increases genomic instability, resulting in uncontrolled cell growth and sometimes eventually tumorigenesis, such as cancer.
If signaling from outside the nucleus and nutritional conditions are favorable, cells become larger in size in the G1 phase and then enter the cell cycle. The cell cycle starts at the G1 checkpoint, which is called START in yeast and the restriction point in mammals. After passing this stage, if there is no specific disturbance, cells progress automatically through the four-phase cell cycle to duplicate their genomes and to divide. In detail, in mammalian cells, the G1 phase, having a checkpoint, is the preparation period for creating new cells. At this stage, if growth factors and sufficient nutrients are not supplied to cells, cells stops progressing through the cell cycle and enter the quiescent phase, G0. In contrast, if sufficient nutrients are supplied and various growth factors are provided, cells enter the S phase. During the S phase, cells duplicate their DNA to have two copies of the chromosome, and synthesize several cytoplasmic factors needed to split themselves into two daughter cells. After the S phase is completed, cells enter the G2 phase, which is called the second checkpoint. During the G2 phase, DNA replication is regulated and completed, and cells prepare to undergo mitosis (the M phase). A variety of factors required for cell organization are produced during this phase. After factors required for division into two daughter cells are sufficiently synthesized, cells progress to the M phase, in which substantial cell division occurs. The M phase is the shortest and most dramatic stage among the four phases of the cell cycle. That is because the two pairs of chromosomes are segregated toward opposite poles of cells to thus divide the cells into two daughter cells. These events are a process that all cells undergo in order to grow and divide themselves into two cells, and are thus very important for maintaining the cell's life. Therefore, the studies on the cell cycle and the development of modulators for the cell cycle are essential for the understanding of cell growth mechanisms and the development of preventive and therapeutic agents for cancer caused by abnormalities in the cell cycle (Marcos Malumbres and Mariano Barbacid, Nature Review Cancer 2001, 1, 222-231).
As noted above, mammalian cell growth can be regulated by controlling the first checkpoint in the G1 phase or the second checkpoint in the G2/M phase. Aberrant progression of the two checkpoints is associated with cellular aging or the development of diseases, such as cancer. Cyclins D1, D2 and D3 play important roles at the cell cycle checkpoints. The D-type cyclins are associated with cyclin-dependant kinase (CDK) 2, 4 or 6 to regulate the activity of the enzyme, and protein phosphatases, such as CDC25, which dephosphorylate phosphorylated proteins, are very important regulators in the entire cell cycle. Based on the previous findings, various cell cycle regulators have been developed as therapeutic agents for stubborn diseases, such as tumors (Peter L Toogood, Current Opinion in Chemical Biology 2002, 6, 472-478).
Cinnamaldehyde derivatives have been reported to have anticancer activity, but have very low solubility in water, which limits their application as anticancer agents. For example, benzoyloxy cinnamaldehyde exhibits good anticancer activity in cells as well as when administered intraperitoneally to animals. However, due to its very low water solubility, the compound cannot be applied to intravenous administration and has greatly decreased anticancer activity when administered orally (Han, D. C., et al., J. Biol. Chem. 2004, 279, 6911-6920). Although various cinnamaldehyde derivatives have been developed, they do not have good anticancer activity when applied to animals due to their low water solubility (Shin D. S. et al., Bioorganic & Medicinal Chemistry Letters 17 (2007) 5423.5427; Bioorganic & Medicinal Chemistry 14 (2006) 2498.2506; Byoung-Mog Kwon, et al., U.S. Pat. No. 6,949,682, 2005; Korean Pat. No. 10-0668171, filed by Byoung-Mog Kwon, et al.).
In this regard, the present inventors have developed novel cinnamaldehyde derivatives or pharmaceutically acceptable salts thereof, which arrest the cell cycle of cancer cells in G2/M phase to inhibit the abnormal growth of the cells and thus have good anticancer activity, thereby leading to the present invention.